Crystalline form of an anxiolytic compound

ABSTRACT

The present invention provides a crystalline Form B of compound 1, and pharmaceutically compositions thereof. The present invention also provides methods of treating a disease (e.g., a disease of the central nervous system) using the pharmaceutical compositions.

FIELD OF THE INVENTION

The present invention relates generally to a crystalline form of ananxiolytic compound and methods and uses of the crystalline form intherapy and to methods for preparing the crystalline form.

BACKGROUND OF THE INVENTION

Polymorphism denotes the existence of more than one crystal structure ofa chemical entity. For any specific chemical entity it is not readilypredictable that it will exhibit polymorphism. In the instance when thechemical entity is a drug, the ability of the chemical entity to existin more than one crystal form can have a profound effect on the shelflife, solubility, formulation properties, and/or processing propertiesof the drug. Furthermore, the biological action of the drug can beaffected by the polymorphism. Different crystalline forms can possessvarying rates of uptake in the body, leading to lower or higherbiological activity than required. An undesired polymorph may even showtoxicity. Therefore the occurrence of an unknown polymorphic form duringmanufacture and processing of a drug can have a profound impact.

It is therefore important to be able to understand and controlpolymorphism. Predicting any possible polymorphs for a drug can diminishthe possibility of contamination during a drug's manufacture or storageby other polymorphic forms.

Also, understanding which crystal structures are possible in some casesallows researchers to maximize the desired properties of a compound,such as solubility, formulation properties, processing properties, andshelf life. Understanding these factors early in the development of anew drug may mean a more active, more stable, or more cheaplymanufactured drug.

SUMMARY OF THE INVENTION

U.S. Pat. No. 8,293,737, the entirety of which is incorporated herein byreference, describes certain 1,8-naphthyridin-4(1H)-one compounds whichare useful as anxiolytic agents. Such compounds include1-ethyl-6-(indan-2-ylamino)-3-(morpholine-4-carbonyl)-1,8-naphthyridin-4-one(compound 1).

Compound 1 possesses anxiolytic activity without sedative side effectsand therefore represents an attractive alternative to the1,4-benzodiazepine class of anxiolytics such as diazepam.

A polymorph of compound 1 has been discovered and named Form B, andcompositions thereof, are useful as therapeutics and in the preparationof pharmaceutical compositions and exhibit desirable characteristics forsuch purposes. In general, Form B, and pharmaceutical compositionsthereof, are useful for treating or lessening the severity of a varietyof diseases or disorders described herein (e.g., an anxiety disorder).Form B is a stable crystalline hemihydrate form of compound 1. Form Bcan be characterized using various techniques as described hereinincluding, but not limited to, x-ray powder diffraction, Ramanspectroscopy, differential scanning calorimetry, dynamic vapor sorption,and thermogravimetric Fourier-transfor infrared thermogram.

Also provided herein is a pharmaceutical composition comprising Form Bof compound 1 and optionally an additional ingredient selected frompharmaceutically acceptable carriers, diluents, and excipients.

Also provided herein are methods of treating various diseases,disorders, or conditions comprising administering to a subject Form B ofcompound 1, or a pharmaceutical composition thereof as described herein.

Also provided herein are uses of Form B of compound 1, or apharmaceutical composition thereof as described herein for treatingvarious diseases, disorders, or conditions.

Also provided herein are uses of Form B of compound 1, or apharmaceutical composition thereof as described herein in themanufacture of a medicament for treating various diseases, disorders, orconditions.

Definitions

The term “solvate” refers to forms of a compound (e.g., compound 1) thatare associated with a solvent, usually by a solvolysis reaction. Thisphysical association may include hydrogen bonding. Conventional solventsinclude water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether,and the like. In certain embodiments, solvates are formed using Class 3solvents. Categories of solvents are defined in, for example, theInternational Conference on Harmonization of Technical Requirements forRegistration of Pharmaceuticals for Human Use (ICH), “Impurities:Guidelines for Residual Solvents, Q3C(R3), (November 2005). A compoundmay be prepared, e.g., in crystalline form, and may be solvated.Suitable solvates include pharmaceutically acceptable solvates andfurther include both stoichiometric solvates and non-stoichiometricsolvates. In certain instances, the solvate will be capable ofisolation, for example, when one or more solvent molecules areincorporated in the crystal lattice of a crystalline solid. “Solvate”encompasses both solution-phase and isolable solvates. Representativesolvates include hydrates, ethanolates, and methanolates.

The term “hydrate,” refers to a compound (e.g., compound 1) which isassociated with water. Typically, the number of the water moleculescontained in a hydrate of a compound is in a definite ratio to thenumber of the compound molecules in the hydrate. Hydrates include bothstoichiometric hydrates and non-stoichiometric hydrates. Therefore, ahydrate of a compound may be represented, for example, by the generalformula R.xH₂O, wherein R is the compound and wherein x is a numbergreater than 0. A given compound may form more than one type ofhydrates, including, e.g., monohydrates (stoichiometric, x is 1), lowerhydrates (non-stoichiometric, x is a number greater than 0 and smallerthan 1, e.g., hemihydrates (R.0.5H₂O)), and polyhydrates(non-stoichiometric, x is a number greater than 1, e.g., dihydrates(R.2H₂O) and hexahydrates (R.6H₂O)).

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers”.

The term “polymorphs” refers to a crystalline form of a compound (e.g.,compound 1), or a hydrate or solvate thereof, in a particular crystalpacking arrangement. All polymorphs have the same elemental composition.The term “crystalline,” as used herein, refers to a solid state formwhich consists of orderly arrangement of structural units. Differentcrystalline forms of the same compound, or a hydrate, or solvatethereof, arise from different packing of the molecules in the solidstate, which results in different crystal symmetries and/or unit cellparameter. Different crystalline forms usually have different X-raydiffraction patterns, infrared spectra, melting points, density,hardness, crystal shape, optical and electrical properties, stability,and solubility. Recrystallization solvent, rate of crystallization,storage temperature, and other factors may cause one crystalline form todominate. Various polymorphs of a compound, or a hydrate or solvatethereof, can be prepared by crystallization under different conditions.

As used herein, the term “impurity” refers to extraneous matter includedin a compound (e.g., Form B of compound 1). Extraneous matter includesone or more substances that are different from the compound. In certainembodiments, the extraneous matter is undesired extraneous matter. Forexample, when an anhydrous compound is desired, the solvent (e.g.,water) included in the compound is an impurity. When a crystallinecompound is desired, an amorphous form of the compound included in thecompound is an impurity. When certain polymorph of a compound isdesired, a different polymorph of the compound included in the compoundis an impurity. The term “substantially free of impurities” means that acompound (e.g., Form B of compound 1), contains no significant amount ofextraneous matter (e.g., undesired extraneous matter). What amount ofthe extraneous matter constitutes a significant amount depends on thesubject matter and is understood in the art. In certain embodiments,about 1 wt %, about 2 wt %, about 3 wt %, about 5 wt %, about 7 wt %, orabout 10 wt % of extraneous matter in a compound is a significant amountof extraneous matter.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g., infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult, or senior adult)) and/or othernon-human animals, for example, mammals (e.g., primates (e.g.,cynomolgus monkeys, rhesus monkeys); commercially relevant mammals suchas cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds(e.g., commercially relevant birds such as chickens, ducks, geese,and/or turkeys). In certain embodiments, the animal is a mammal. Theanimal may be a male or female at any stage of development. The animalmay be a transgenic animal or genetically engineered animal. In certainembodiments, the subject is a non-human animal. In certain embodiments,the animal is fish.

The terms “administer,” “administering,” or “administration,” as usedherein, refers to implanting, absorbing, ingesting, injecting, inhaling,or otherwise introducing a compound (e.g., Form B of compound 1) orpharmaceutical composition thereof, in or on a subject.

As used herein, the terms “in combination” and “co-administration” canbe used interchangeably to refer to the use of more than one therapy(e.g., one or more prophylactic and/or therapeutic agents). The use ofthe terms does not restrict the order in which therapies (e.g.,prophylactic and/or therapeutic agents) are administered to a subject.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a “pathological condition” (e.g., a disease, disorder, orcondition, or one or more signs or symptoms thereof). In someembodiments, treatment may be administered after one or more signs orsymptoms have developed or have been observed. In other embodiments,treatment may be administered in the absence of signs or symptoms of thedisease or condition. For example, treatment may be administered to asusceptible individual prior to the onset of symptoms. Treatment mayalso be continued after symptoms have resolved, for example, to delay orprevent recurrence.

The terms “prevention,” “prevent,” and “preventing,” as used herein,refer to administering a medicament (e.g., Form B of compound 1 or apharmaceutical composition thereof) beforehand to avert or forestall theappearance of one or more symptoms of a disease or disorder. The personof ordinary skill in the medical art recognizes that the terms“prevention,” “prevent,” and “preventing” are not absolute terms. In themedical art these terms are understood to refer to the prophylacticadministration of a medicament to substantially diminish the likelihoodor seriousness of a condition, or symptom of the condition, and this isthe sense intended in this disclosure.

As used herein, the terms “condition,” “disease,” and “disorder” areused interchangeably.

An “effective amount” of a compound described herein refers to an amountsufficient to elicit the desired biological response, e.g., treating acondition. As will be appreciated by those of ordinary skill in thisart, the effective amount of a compound described herein may varydepending on such factors as the desired biological endpoint, thepharmacokinetics of the compound, the condition being treated, the modeof administration, and the age and health of the subject. An effectiveamount encompasses therapeutic and prophylactic treatment. For example,in treating an anxiety disorder, an effective amount of an inventivecompound may provide a therapeutic and/or prophylactic benefit in thetreatment and/or prevention of the anxiety disorder or to delay orminimize one or more symptoms associated with the anxiety disorder.

A “therapeutically effective amount” of a compound described herein isan amount sufficient to provide a therapeutic benefit in the treatmentof a condition (e.g., an anxiety disorder) or to delay or minimize oneor more symptoms associated with the condition. A therapeuticallyeffective amount of a compound means an amount of therapeutic agent,alone or in combination with other therapies, which provides atherapeutic benefit in the treatment of the condition. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of the condition,or enhances the therapeutic efficacy of another therapeutic agent.

A “prophylactically effective amount” of a compound described herein isan amount sufficient to prevent a condition (e.g., an anxiety disorder),or one or more symptoms associated with the condition or prevent itsrecurrence. A prophylactically effective amount of a compound means anamount of a therapeutic agent, alone or in combination with otheragents, which provides a prophylactic benefit in the prevention of thecondition. The term “prophylactically effective amount” can encompass anamount that improves overall prophylaxis or enhances the prophylacticefficacy of another prophylactic agent.

The term “neurite” refers to any projection from the cell body of aneuron. This projection can be either an axon or a dendrite. Neuritesare often packed with microtubule bundles, the growth of which isstimulated by Nerve Growth Factor (NGF), as well as tau proteins, MAP1,and MAP2. The neural cell adhesion molecule N-CAM simultaneouslycombines with another N-CAM and a fibroblast growth factor receptor tostimulate the tyrosine kinase activity of that receptor to induce thegrowth of neurites.

A disease “responsive to neurite outgrowth” is a disease, disorder, orcondition which may be ameliorated by enhancement of neurite outgrowth.Diseases responsive to neurite outgrowth include neurodegenerativediseases (e.g., multiple sclerosis and a Parkinsonian related disorder)and diseases that involve neural damage that include wound healing,spinal cord injury, and peripheral nerve disorders.

The present application refers to various issued patent, publishedpatent applications, journal articles, and other publications, all ofwhich are incorporated herein by reference.

The details of one or more embodiments of the invention are set forthherein. Other features, objects, and advantages of the invention will beapparent from the Detailed Description, the Figures, the Examples, andthe Claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an X-Ray Powder Diffraction (XRPD) pattern of Form B.

FIG. 2 depicts a Fourier-Transform Raman (FT-Raman) spectrum of Form B.

FIG. 3 depicts a Differential Scanning Calorimetry (DSC) thermogram ofForm B.

FIG. 4 depicts a Dynamic Vapor Sorption (DVS) isotherm of Form B.

FIG. 5 depicts a Thermogravimetric Fourier-Transform Infrared (TG-FTIR)thermogram of Form B.

FIG. 6 depicts a Proton Nuclear Magnetic Resonance (¹H-NMR) spectrum ofForm B.

FIGS. 7A-B depict microscopic images of Form B recorded without (FIG.7A) and with (FIG. 7B) crossed polarizers. Compound 1 appears dark inthe left image and bright in the right image.

FIG. 8 depicts XRPD patterns of Form B before (top) and after (bottom)drying. The patterns have been scaled and offset in the y-direction forpurposes of comparison.

FIG. 9 depicts a TG-FTIR thermogram of a dried sample obtained from FormB.

FIG. 10 depicts an infrared (IR) spectrum of Form B.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

Compound 1 (1-ethyl-6-(indan-2-ylamino)-3-(morpholine-4-carbonyl)-1,8-naphthyridin-4-one) has been reported toelicit an anxiolytic effect. Compound 1 has shown significant potentialfor the treatment of a variety of disorders of the central nervoussystem (CNS), such as anxiety disorders. See, e.g., U.S. Pat. No.8,293,737.

Solid Form

In some embodiments, it would be desirable to provide a crystallinepolymorph of compound 1 that, as compared to the amorphous compound 1,imparts improved physical characteristics such as stability and/or easeof formulation. Accordingly, provided herein is a crystalline form(denoted Form B) of compound 1. Form B is a hemihydrate of compound 1.Form B is stable upon drying, and other solvates of compound 1 were lessstable upon drying. For example, solvates of methanol, ethanol,isopropanol, tetrahydofuran (THF), and dioxane either changed from orshowed a reduction in crystallinity upon drying. In some embodiments,Form B has a water content of about 2.0 wt %. Form B is substantiallynon-hygroscopic. In contrast, anhydrous forms of compound 1 were foundto show indications of hygroscopicity. Form B was also found to be morestable than an anhydrous form of compound 1. In a competitive slurryexperiment there was a tendency for the anhydrous form to convert toForm B.

In some embodiments, Form B is substantially free of impurities. In someembodiments, Form B is 99% free of impurities. In some embodiments, FormB is 97% free of impurities. In some embodiments, Form B is 95% free ofimpurities. In some embodiments, Form B is 92% free of impurities. Insome embodiments, Form B is 90% free of impurities. In certainembodiments, the impurities include extraneous matter, such as a saltforming acid, residual solvents, or any other impurities that may resultfrom the preparation, and/or isolation, of compound 1. In someembodiments, Form B is substantially free of amorphous compound 1. Insome embodiments, Form B is substantially free of another crystallineform of compound 1. In some embodiments, Form B is substantially free ofa salt of compound 1. In some embodiments, Form B is substantially freeof a non-water solvate of compound 1. In some embodiments, Form B isobtained from mixture of methanol and water.

Different solid forms of a compound typically differ in their physicaland chemical properties based on the arrangement of the molecules in thesolid form (e.g., the arrangement of the molecule in the crystallattice). A given substance may give rise to a variety of solid forms,in particular a variety of crystalline forms, wherein each form hasdifferent and distinct physical and chemical properties, such assolubility profiles, thermodynamic and chemical stabilities, meltingpoints, Raman spectra, and/or x-ray diffraction peaks.

Form B can be characterized by one or more of the characteristicsdescribed herein including, but not limited to, XRPD diffraction patternand/or peaks, Raman spectrum and/or peaks, DSC thermogram, DVS isotherm,TG-FTIR thermogram, IR spectrum and/or peaks, appearance, melting point,solubility, and stability. In certain embodiments, Form B ischaracterized by XRPD diffraction pattern and/or peaks and Ramanspectrum and/or peaks. In certain embodiments, Form B is characterizedby XRPD diffraction pattern and/or peaks, Raman spectrum and/or peaks,and at least one other technique as described herein (e.g., DSCthermogram, DVS isotherm, TG-FTIR thermogram, melting point).

In some embodiments, Form B is characterized by an X-ray powderdiffraction pattern substantially similar to the one depicted in FIG. 1.In some embodiments, Form B is characterized in that it has one or morepeaks in its X-ray powder diffraction pattern selected from those inTable 1. In some embodiments, Form B is characterized by at least one,at least two, at least three, at least four, at least five, at leastsix, at least seven, at least eight, at least nine, at least ten, atleast eleven, at least twelve, at least thirteen, at least fourteen, atleast fifteen, at least sixteen, at least seventeen, at least eighteen,at least nineteen, at least twenty, at least twenty-one, at leasttwenty-two, at least twenty-three, at least twenty-four, at leasttwenty-five, at least twenty-six, at least twenty-seven, at leasttwenty-eight, at least twenty-nine, at least thirty, at leastthirty-one, at least thirty-two, at least thirty-three, or at leastthirty-four peaks in its X-ray powder diffraction pattern selected fromthose in Table 1. In some embodiments, Form B of compound 1 ischaracterized in that it has one or more peaks in its X-ray powderdiffraction pattern selected from the strong and very strong peaks inTable 1. In some embodiments, Form B of compound 1 is characterized inthat it has all the peaks in its X-ray powder diffraction patternselected from the strong and very strong peaks in Table 1. In someembodiments, Form B of compound 1 is characterized in that it has one ormore peaks in its X-ray powder diffraction pattern selected from thevery strong peaks in Table 1. In some embodiments, Form B of compound 1is characterized in that it has all the peaks in its X-ray powderdiffraction pattern selected from the very strong peaks in Table 1. Insome embodiments, Form B of compound 1 is characterized in that it hasboth very strong peaks listed in Table 1 (i.e., 19.02 and 23.16 angletheta-2).

TABLE 1 X-ray powder diffraction pattern. Angle d value Intensity2-Theta ° Angstrom (relative) Intensity % 6.05 14.6 m 16 6.48 13.6 w 108.78 10.1 w 11 9.00 9.8 m 22 12.16 7.3 m 23 13.94 6.3 s 31 14.25 6.2 m25 14.52 6.1 s 55 16.27 5.45 s 60 16.60 5.34 s 42 17.62 5.03 s 57 18.094.90 m 18 18.31 4.84 m 17 18.76 4.73 s 32 19.02 4.66 vs 79 19.29 4.60 s43 19.64 4.52 s 54 20.78 4.27 m 23 20.95 4.24 m 17 22.32 3.98 s 60 22.773.90 s 50 23.02 3.86 s 53 23.16 3.84 vs 100 23.39 3.80 m 17 24.42 3.64 m30 25.53 3.49 m 25 25.97 3.43 w 12 26.82 3.32 m 28 27.51 3.24 w 14 29.693.01 w 12 30.17 2.96 w 12 31.10 2.87 w 11 31.65 2.83 w 11 34.96 2.56 w11

The terms used in the tables herein have the following meanings: Theterm “vs” stands for “very strong.” The term “s” stands for “strong.”The term “m” stands for “medium.” The term “w” stands for “weak.” Theterm “vw” stands for “very weak.”

In some embodiments, Form B is characterized by one or more peaks in itsX-ray powder diffraction pattern selected from those in Table 2. In someembodiments, Form B is characterized by at least one, at least two, atleast three, at least four, at least five, at least six, at least seven,at least eight, at least nine, at least ten, at least eleven, at leasttwelve, or at least thirteen peaks in its X-ray powder diffractionpattern selected from those in Table 2. In some embodiments, thecharacteristic peaks include at least the two very strong peaksindicated in Table 2. In some embodiments, Form B is characterized bythe two very strong peaks indicated in Table 2, and at least one, atleast two, at least three, at least four, at least five, at least six,at least seven, at least eight, at least nine, at least ten, at leasteleven, at least twelve, or at least thirteen of the other strong peaksin its X-ray powder diffraction pattern selected from those in Table 2.

TABLE 2 Select characteristic peaks from the X-ray powder diffractionpattern. Angle d value Intensity 2-Theta ° Angstrom (relative) Intensity% 13.94 6.3 s 31 14.52 6.1 s 55 16.27 5.45 s 60 16.60 5.34 s 42 17.625.03 s 57 18.76 4.73 s 32 19.02 4.66 vs 79 19.29 4.60 s 43 19.64 4.52 s54 22.32 3.98 s 60 22.77 3.90 s 50 23.02 3.86 s 53 23.16 3.84 vs 100

For instance, in one embodiment Form B is characterised by the 6 peaks(from Table 2) with the Angle 2-Theta° values of 13.94, 14.52, 16.27,19.02, 22.32, and 23.16.

In some embodiments, Form B is characterized by a Raman spectrumsubstantially similar to the one depicted in FIG. 2. In someembodiments, Form B is characterized by one or more peaks in its Ramanspectrum selected from those in Table 3. In some embodiments, Form B ischaracterized by at least one, at least two, at least three, at leastfour, at least five, at least six, at least seven, at least eight, atleast nine, at least ten, at least fifteen, at least twenty, at leastthirty, at least forty, at least fifty, or at least sixty peaks in itsRaman spectrum selected from those in Table 3.

In some embodiments, Form B is characterized by (1) a Raman spectrumsubstantially similar to the one depicted in FIGS. 2 and (2) an X-raypowder diffraction pattern substantially similar to the one depicted inFIG. 1. In some embodiments, Form B is characterized by (1) a Ramanspectrum substantially similar to the one depicted in FIGS. 2 and (2)one or more peaks in its X-ray powder diffraction pattern selected fromthose in Table 1. In some embodiments, Form B is characterized by (1) aRaman spectrum substantially similar to the one depicted in FIGS. 2; and(2) one or more peaks in its X-ray powder diffraction pattern selectedfrom those in Table 2. In some embodiments, Form B is characterized by(1) a Raman spectrum substantially similar to the one depicted in FIGS.2; and (2) the two very strong peaks indicated in Table 2 and at leastone, at least two, at least three, at least four, at least five, atleast six, at least seven, at least eight, at least nine, at least ten,or at least eleven of the other strong peaks in its X-ray powderdiffraction pattern selected from those in Table 2. In some embodiments,Form B is characterized by (1) at least one, at least two, at leastthree, at least four, at least five, at least six, at least seven, atleast eight, at least nine, at least ten, at least fifteen, at leasttwenty, at least thirty, at least forty, at least fifty, or at leastsixty peaks in its Raman spectrum selected from those in Table 3; and(2) one or more peaks in its X-ray powder diffraction pattern selectedfrom those in Table 2. In some embodiments, Form B 1 is characterized by(1) at least one, at least two, at least three, at least four, at leastfive, at least six, at least seven, at least eight, at least nine, atleast ten, at least fifteen, at least twenty, at least thirty, at leastforty, at least fifty, or at least sixty peaks in its Raman spectrumselected from those in Table 3; and (2) the two very strong peaksindicated in Table 2 and at least one, at least two, at least three, atleast four, at least five, at least six, at least seven, at least eight,at least nine, at least ten, or at least eleven of the other strongpeaks in its X-ray powder diffraction pattern selected from those inTable 2.

TABLE 3 Raman spectrum. Wavenumber Absolute Normalized (cm⁻¹) IntensityIntensity (%) 3322 0.018 3.6 3070 0.105 20.9 3007 0.097 19.3 2993 0.13126.1 2963 0.171 34.1 2931 0.162 32.3 2910 0.121 24.1 2871 0.070 13.92842 0.100 19.9 1636 0.502 100.0 1611 0.432 86.1 1604 0.457 91.0 15080.101 20.1 1497 0.108 21.5 1478 0.137 27.3 1459 0.101 20.1 1446 0.17835.5 1425 0.153 30.5 1393 0.184 36.7 1355 0.160 31.9 1344 0.224 44.61319 0.083 16.5 1304 0.084 16.7 1285 0.107 21.3 1271 0.119 23.7 12430.068 13.5 1225 0.085 16.9 1208 0.096 19.1 1150 0.061 12.2 1136 0.06412.7 1112 0.058 11.6 1095 0.067 13.3 1064 0.078 15.5 1039 0.086 17.11025 0.170 33.9 1010 0.087 17.3 996 0.087 17.3 957 0.043 8.6 943 0.0459.0 849 0.139 27.7 819 0.059 11.8 810 0.059 11.8 789 0.255 50.8 7410.196 39.0 713 0.091 18.1 681 0.096 19.1 603 0.084 16.7 585 0.060 12.0555 0.070 13.9 501 0.075 14.9 484 0.096 19.1 446 0.076 15.1 419 0.10420.7 372 0.080 15.9 349 0.076 15.1 316 0.090 17.9 261 0.100 19.9 2340.132 26.3 185 0.141 28.1 141 0.167 33.3

In some embodiments, Form B is characterized by one or more peaks in itsRaman spectrum selected from those in Table 4. In some embodiments, FormB is characterized by at least one, at least two, at least three, atleast four, at least five, at least six, at least seven, at least eight,at least nine, at least ten, or at least eleven peaks in its Ramanspectrum selected from those in Table 4. In some embodiments, Form B ischaracterized by (1) one or more peaks in its Raman spectrum selectedfrom those in Table 4; and (2) an X-ray powder diffraction patternsubstantially similar to the one depicted in FIG. 1. In someembodiments, Form B is characterized by (1) one or more peaks in itsRaman spectrum selected from those in Table 4; and (2) one or more peaksin its X-ray powder diffraction pattern selected from those in Table 1.In some embodiments, Form B is characterized by (1) one or more peaks inits Raman spectrum selected from those in Table 4; and (2) one or morepeaks in its X-ray powder diffraction pattern selected from those inTable 2. In some embodiments, Form B is characterized by (1) at leastone, at least two, at least three, at least four, at least five, atleast six, at least seven, at least eight, at least nine, at least ten,or at least eleven peaks in its Raman spectrum selected from those inTable 4; and (2) one or more peaks in its X-ray powder diffractionpattern selected from those in Table 2.

TABLE 4 Select characteristic peaks from the Raman spectrum. WavenumberAbsolute Normalized (cm⁻¹) Intensity Intensity (%) 1636 0.502 100.0 16110.432 86.1 1604 0.457 91.0 1446 0.178 35.5 1425 0.153 30.5 1393 0.18436.7 1355 0.160 31.9 1344 0.224 44.6 1025 0.170 33.9 789 0.255 50.8 7410.196 39.0

For instance, in some embodiments Form B is characterised by the 8 peaks(from Table 4) with the following wavenumbers (cm⁻¹) 1636, 1604, 1446,1425, 1393, 1355, 1025, and 741.

In some embodiments, Form B is characterized by an IR spectrumsubstantially similar to the one depicted in FIG. 10. In someembodiments, Form B is characterized by one or more peaks in its IRspectrum selected from those in Table 9.

TABLE 9 IR spectrum. No. Position Intensity No. Position Intensity No.Position Intensity  1 3389.28 18.8803  2 3321.78 15.2998  3 3066.2643.3187  4 3033.48 52.327  5 2991.05 44.2454  6 2970.8 36.2048  7 2960.235.8651  8 2928.38 28.2099  9 2839.67 28.5464 10 2765.42 68.3886 112707.57 71.199 12 2684.43 72.4374 13 2588.97 74.7507 14 2204.24 79.212315 1976.68 81.6905 16 1954.5 80.4172 17 1921.72 81.2251 18 1847.4780.7596 19 1807.94 79.7842 20 1680.66 59.904 21 1632.45 1.12286 221593.88 0.229197 23 1493.6 0.785332 24 1476.24 5.24501 25 1458.8916.6916 26 1431.89 12.9634 27 1390.42 25.9737 28 1379.82 30.7322 291341.25 14.0312 30 1318.11 20.5376 31 1301.72 49.2933 32 1269.9 6.9171233 1244.83 7.5622 34 1216.86 21.9545 35 1209.15 26.0253 36 1128.1555.6498 37 1113.69 4.73713 38 1093.44 42.0985 39 1068.37 39.536 401036.55 51.1775 41 1023.05 68.0011 42 1005.7 62.1369 43 994.125 41.565544 955.555 72.4243 45 940.128 55.4283 46 905.415 77.3957 47 889.98748.5083 48 848.525 48.9604 49 808.992 37.3274 50 789.707 46.8949 51754.995 16.0235 52 743.424 52.7696 53 710.64 66.7717 54 679.785 46.589855 601.682 34.7989 56 554.434 68.6904 57 521.65 76.6701 58 477.29661.4961 59 442.583 77.4332 60 428.12 78.2972 61 410.763 75.3479

In some embodiments Form B is characterised by the 5 peaks (from Table9) with the following wavenumbers (cm⁻¹) 1632.45, 1593.88, 1244.83,754.995, and 601.682.

In some embodiments, Form B is characterized by (1) an XRPD patternshaving peaks shown in Table 2a, (2) Raman spectrum with characteristicpeaks shown in the Table 3a, (3) IR spectrum with characteristic peaksshown Table 9a, and (4) a DSC thermogram with an endotherm having a peaktemperature (_(Tmax)) of about 176° C.

TABLE 2a Select characteristic peaks the XRPD spectrum of Form B Angle dvalue Intensity 2-Theta ° Angstrom (relative) Intensity % 13.94 6.3 s 3123.16 3.84 vs 100

TABLE 3a Select characteristic peaks from the Raman spectrum of form B.Wavenumber Normalized Intensity (cm⁻¹) Absolute Intensity (%) 1636 0.502100.0 1604 0.457 91.0 741 0.196 39.0

TABLE 9a Select characteristic Peaks from the IR Spectrum of form BWavenumber Cm⁻¹ % T 1632.45 1.12286 1593.88 0.229197 1244.83 7.5622754.995 16.0235

In some embodiments, Form B is characterized by (1) an XRPD patternshaving peaks shown in Table 2b, (2) Raman spectrum with characteristicpeaks shown in the Table 3b, (3) IR spectrum with characteristic peaksshown Table 9b, and (4) a DSC thermogram with an endotherm having a peaktemperature (T_(max)) of about 176° C.

TABLE 2b Select characteristic peaks the XRPD spectrum of Form B Angle dvalue Intensity 2-Theta ° Angstrom (relative) Intensity % 13.94 6.3 s 3119.02 4.66 vs 79 23.16 3.84 vs 100

TABLE 3b Select characteristic peaks from the Raman spectrum of form B.Wavenumber Normalized Intensity (cm⁻¹) Absolute Intensity (%) 1636 0.502100.0 1604 0.457 91.0 1025 0.170 33.9 741 0.196 39.0

TABLE 9b Select characteristic Peaks from the IR Spectrum of form BWavenumber (cm⁻¹) % T 1632.45 1.12286 1593.88 0.229197 1244.83 7.5622754.995 16.0235 601.682 34.7989

In some embodiments, Form B is characterized by (1) an XRPD patternshaving peaks shown in Table 2c, (3) IR spectrum with characteristicpeaks shown Table 9c, and (3) a DSC thermogram with an endotherm havinga peak temperature (T_(max)) of about 176° C.

TABLE 2c Select characteristic peaks the XRPD spectrum of Form B Angle dvalue Intensity 2-Theta ° Angstrom (relative) Intensity % 13.94 6.3 s 3119.02 4.66 vs 79 23.16 3.84 vs 100

TABLE 9c Select characteristic Peaks from the IR Spectrum of form BWavenumber (cm⁻¹) % T 1632.45 1.12286 1593.88 0.229197 754.995 16.0235601.682 34.7989

In some embodiments, Form B is characterised by the following:

-   (i) Characteristic peaks from the XRPD spectrum of Form B

Angle d value Intensity 2-Theta ° Angstrom (relative) Intensity % 13.946.3 s 31 14.52 6.1 s 55 16.27 5.45 s 60 19.02 4.66 vs 79 22.32 3.98 s 6023.16 3.84 vs 100, and

-   (ii) Characteristic peaks from the Raman spectrum of Form B.

Wavenumber Normalized Intensity (cm⁻¹) Absolute Intensity (%) 1636 0.502100.0  1604 0.457 91.0 1446 0.178 35.5 1425 0.153 30.5 1393 0.184 36.71355 0.160 31.9 1025 0.170 33.9 741 0.196  39.0,and

-   (iii) Characteristic Peaks from the IR Spectrum of Form B

Wavenumber (cm⁻¹) % T 1632.45  1.12286 1593.88   0.229197 1244.83 7.5622 754.995 16.0235 601.682  34.7989,and

-   (iv) a DSC thermogram with an endotherm having a peak temperature    (T_(max)) of about 176° C.

In some embodiments, Form B has a DSC thermogram substantially similarto the one depicted in FIG. 3. In some embodiments, Form B ischaracterized in that it has a DSC thermogram with an endotherm having apeak temperature (T_(max)) of about 176° C. In some embodiments, Form Bis characterized in that it has a DSC thermogram with a ΔH of about 105J/g. In some embodiments, Form B is characterized in that it has a glasstransition (T_(g)) of about 71° C. after quench cooling. In someembodiments, Form B is characterized in that it has a ΔCp of about 0.48J/g after quench cooling.

In some embodiments, Form B has a DVS isotherm substantially similar tothe one depicted in FIG. 4. In some embodiments, Form B is characterizedin that it has a Δm of 0.1 wt % from 50% relative humidity (r.h.) to 85%r.h.

In some embodiments, Form B has a TG-FTIR thermogram substantiallysimilar to the one depicted in FIG. 5. In some embodiments, Form B ischaracterized in that it losses about 2.0 wt % or 0.5 equivalent (eq.)of H₂O after the temperature of Form B is increased from about 100° C.to about 230° C.

In some embodiments, Form B has a microscopic image substantiallysimilar to the one depicted in FIG. 7A or FIG. 7B. In some embodiments,Form B is granular crystals.

In some embodiments, Form B has an observed melting point of about155-168° C.

In some embodiments, Form B is stable for at least about 1 month, atleast about 2 months, at least about 4 months, at least about 6 months,at least about 12 months, at least about 18 months, at least about 24months, or at least about 3 years at about 25° C. and about 60% relativehumidity. In some embodiments, Form B has substantially the same XRPDpattern post storage for at least about 1 month, at least about 2months, at least about 4 months, at least about 6 months, at least about12 months, at least about 18 months, at least about 24 months, or atleast about 3 years at about 25° C. and about 60% relative humidity. Insome embodiments, Form B has substantially the same IR spectrum poststorage for at least about 1 month, at least about 2 months, at leastabout 4 months, at least about 6 months, at least about 12 months, atleast about 18 months, at least about 24 months, or at least about 3years at about 25° C. and about 60% relative humidity.

In some embodiments, Form B is stable for at least about 1 month, atleast about 2 months, at least about 4 months, at least about 6 months,at least about 8 months, at least about 10 months, at least about 12months, at least about 18 months, or at least about 24 months at about40° C. and about 75% relative humidity. In some embodiments, Form B hassubstantially the same XRPD pattern post storage for at least about 1month, at least about 2 months, at least about 4 months, at least about6 months, at least about 8 months, at least about 10 months, at leastabout 12 months, at least about 18 months, or at least about 24 monthsat about 40° C. and about 75% relative humidity. In some embodiments,Form B has substantially the same IR spectrum post storage for at leastabout 1 month, at least about 2 months, at least about 4 months, atleast about 6 months, at least about 8 months, at least about 10 months,at least about 12 months, at least about 18 months, or at least about 24months at about 40° C. and about 75% relative humidity.

Pharmaceutical Compositions

In some embodiments, the present invention provides a compositioncomprising crystalline Form B of compound 1 described herein andoptionally a pharmaceutically acceptable excipient. In certainembodiments, the pharmaceutical compositions are useful for treating adisease, disorder, or condition described herein. In certainembodiments, a provided composition is formulated for administration toa subject in need of such composition. In certain embodiments, aprovided composition is formulated for oral administration to a subject.In certain embodiments, a provided composition is formulated into anoral dosage form. In certain embodiments, a provided composition isformulated into a tablet, powder, pill, capsule, or the like, for oralingestion by a subject.

Suitable techniques, carriers, and excipients include those foundwithin, for example, Remington: The Science and Practice of Pharmacy,19^(th) edition, Mack Publishing Company, Easton, Pa. 1995; Hoover, JohnE., Remington's Pharmaceutical Sciences, Mack Publishing Company,Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds., PharmaceuticalDosage Forms, Marcel Decker, New York, N.Y. 1980; and PharmaceuticalDosage Forms and Drug Delivery Systems, 7^(th) edition, LippincottWilliams & Wilkins, 1999, all of which are incorporated herein byreference in their entireties.

In general, doses of provided pharmaceutical compositions employed foradult human treatment are typically in the range of about 0.01 mg toabout 5000 mg per day. In certain embodiments, doses employed for adulthuman treatment are from about 1 mg to about 1000 mg per day. In certainembodiments, a desired dose is conveniently presented in a single doseor in divided doses administered simultaneously (or over a short periodof time) or at appropriate intervals, for example, as two, three, fouror more sub-doses per day.

It will be understood that a specific dosage and treatment regimen forany particular subject may depend on a variety of factors, including theactivity of the specific compound employed, age, body weight, generalhealth, sex, diet, time of administration, rate of excretion, drugcombination, and the judgment of the treating physician and the severityof the particular disease being treated. The amount of a providedcompound in the composition may also depend upon the particular compoundin the composition.

Methods of Preparing Form B

The present invention also provides methods of preparing Form B. Incertain embodiments, methods of preparing Form B comprise mixing asolution of compound 1 in methanol with an aqueous solution of a base toprovide a mixture. In certain embodiments, the methods of preparing FormB further comprise lowering the temperature of the mixture to provide asolid. In certain embodiments, the methods of preparing Form B furthercomprise isolating the solid from the mixture.

Compound 1 useful in the preparation of Form B may be substantially freeof impurities. In certain embodiments, compound 1 useful in thepreparation of Form B is about 90% free of impurities. In certainembodiments, compound 1 useful in the preparation of Form B is about 92%free of impurities. In certain embodiments, compound 1 useful in thepreparation of Form B is about 95% free of impurities. In certainembodiments, compound 1 useful in the preparation of Form B is about 97%free of impurities. In certain embodiments, compound 1 useful in thepreparation of Form B is about 99% free of impurities. In certainembodiments, compound 1 useful in the preparation of Form B is about99.5% free of impurities. In certain embodiments, compound 1 useful inthe preparation of Form B includes compound 2 as an impurity:

Compound 1 may be present in the solution of compound 1 and methanol atany suitable concentration (e.g., about 0.003 kg/L, about 0.01 kg/L,about 0.02 kg/L, about 0.03 kg/L, about 0.04 kg/L, about 0.05 kg/L,about 0.06 kg/L, about 0.08 kg/L, about 0.1 kg/L, about 0.2 kg/L, about0.5 kg/L, or about 1 kg/L), as the solubility of compound 1 permits. Incertain embodiments, the concentration of compound 1 in the solution ofcompound 1 and methanol is about 0.04 kg/L.

The base useful in the preparation of Form B may be any inorganic base.In certain embodiments, the inorganic base is ammonia. In certainembodiments, the inorganic base is ammonium carbonate. In certainembodiments, the inorganic base is ammonium hydroxide. In certainembodiments, the inorganic base is an alkali metal carbonate. In certainembodiments, the inorganic base is Li₂CO₃, Na₂CO₃, K₂CO₃, Rb₂CO₃, orCs₂CO₃. In certain embodiments, the inorganic base is an alkali metalbicarbonate. In certain embodiments, the inorganic base is LiHCO₃,NaHCO₃, KHCO₃, RbHCO₃, or CsHCO₃. In certain embodiments, the inorganicbase is an alkali metal hydroxide. In certain embodiments, the inorganicbase is LiOH, NaOH, KOH, RbOH, or CsOH. In certain embodiments, theinorganic base is an alkaline earth metal carbonate. In certainembodiments, the inorganic base is BeCO₃, MgCO₃, CaCO₃, SrCO₃, or BaCO₃.In certain embodiments, the inorganic base is an alkaline earth metalbicarbonate. In certain embodiments, the inorganic base is Be(HCO₃)₂,Mg(HCO₃)₂, Ca(HCO₃)₂, Sr(HCO₃)₂, or Ba(HCO₃)₂. In certain embodiments,the inorganic base is an alkaline earth metal hydroxide. In certainembodiments, the inorganic base is Be(OH)₂, Mg(OH)₂, Ca(OH)₂, Sr(OH)₂,or Ba(OH)₂. The base useful in the preparation of Form B may also be anorganic base. In certain embodiments, the organic base is an aliphaticamine. In certain embodiments, the organic base is an aromatic amine. Incertain embodiments, the organic base is a primary amine. In certainembodiments, the organic base is a secondary amine. In certainembodiments, the organic base is a tertiary amine. In certainembodiments, the organic base is triethylamine, DIPEA, or DBU. Incertain embodiments, the organic base is substituted pyridine. Incertain embodiments, the organic base is 2,6-lutidine or DMAP. Incertain embodiments, the organic base is unsubstituted pyridine. Thebase may be present in the aqueous solution at any suitableconcentration (e.g., about 0.01 g/L, about 0.03 g/L, about 0.1 g/L,about 0.2 g/L, about 0.3 g/L, about 0.4 g/L, about 0.5 g/L, about 0.7g/L, about 1 g/L, about 3 g/L, about 10 g/L, or about 30 g/L), as thesolubility of the base permits. In certain embodiments, the base ispresent in the aqueous solution at about 0.2 g/L.

In certain embodiments, the solution of compound 1 in methanol issubstantially homogeneous. In certain embodiments, the solution ofcompound 1 in methanol is substantially free of solid materials. Incertain embodiments, the aqueous solution of the base is substantiallyhomogeneous. In certain embodiments, the aqueous solution of the base issubstantially free of solid materials. In certain embodiments, themixture of the inventive methods is a substantially homogeneoussolution. In certain embodiments, the mixture is heterogeneous. Incertain embodiments, the mixture comprises a solid. In certainembodiments, the mixture comprises a solid and a liquid. In certainembodiments, the mixture comprises Form B. In certain embodiments, themixture comprises Form B that is substantially free of impurities.

When the mixture of the inventive methods comprises a solid, the solidmay be isolated from the mixture by a process known in the art, such asby filtration and/or centrifuge. The solid isolated form the mixture mayoptionally be subject to a reduced pressure and/or a suitabletemperature as described herein. In certain embodiments, the solid inthe mixture comprises Form B. In certain embodiments, the solid in themixture comprises Form B that is substantially free of impurities. Incertain embodiments, the solid isolated from the mixture comprises FormB. In certain embodiments, the solid isolated from the mixture comprisesForm B that is substantially free of impurities. In certain embodiments,the solid isolated from the mixture comprises at least 99%, at least99.2%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%,at least 99.8%, at least 99.9%, at least 99.95%, at least 99.99%, atleast 99.995%, or at least 99.999% Form B by weight.

The steps of preparing Form B may be performed at any suitabletemperature, e.g., a suitable temperature of at least about 60° C. andlower than about 65° C. Other ranges are also possible. In certainembodiments, the suitable temperature is about 0° C. In certainembodiments, the suitable temperature is about 23° C. In certainembodiments, the suitable temperature is about 60° C. In certainembodiments, the suitable temperature is about 65° C. A suitabletemperature may be a variable temperature during one or more steps of amethod of the invention. In certain embodiments, the temperature of thesolution of compound 1 in methanol is a suitable temperature describedherein (e.g., about 60 to 65° C.). In certain embodiments, thetemperature of the aqueous solution of the base is a suitabletemperature described herein (e.g., about 60 to 65° C.). The temperatureof the solution of compound 1 in methanol and the temperature of theaqueous solution of the base may be the same or different. In the stepof lowering the temperature of the mixture, the temperature of themixture may be lowered by about 10° C., about 20° C., about 30° C.,about 35° C., about 40° C., about 45° C., about 50° C., about 60° C.,about 65° C., about 70° C., about 80° C., about 90° C., or about 100° C.In certain embodiments, the temperature of the mixture is lowered by atleast about 35 and less than about 45° C. In certain embodiments, themixture is substantially homogeneous before the temperature of it islowered. In certain embodiments, the mixture is substantially free ofsolid materials before the temperature of the mixture is lowered. Incertain embodiments, the mixture is heterogeneous after the temperatureof it is lowered. In certain embodiments, the mixture comprises a solidafter the temperature of the mixture is lowered. In certain embodiments,the mixture comprises a solid and a liquid after the temperature of themixture is lowered.

A suitable condition may also include a suitable pressure under whichone or more steps of the inventive methods are performed. In certainembodiments, the suitable pressure is about 1 atmosphere. A suitablepressure may also be higher or lower than 1 atmosphere (i.e., a reducedpressure). A reduced pressure may be a pressure lower than about 10⁻¹atmosphere, lower than about 10⁻² atmosphere, lower than about 10⁻³atmosphere, lower than about 10⁻⁴ atmosphere, lower than about 10⁻⁵atmosphere, lower than about 10⁻⁶ atmosphere, lower than about 10⁻⁷atmosphere, lower than about 10⁻⁸ atmosphere, lower than about 10⁻⁹atmosphere, lower than about 10⁻¹⁰ atmosphere, or lower than about10^('11) atmosphere.

A suitable condition may also include a suitable atmosphere under whichone or more steps of the inventive methods are performed. In certainembodiments, the suitable atmosphere is air. In certain embodiments, thesuitable atmosphere is an inert atmosphere. In certain embodiments, thesuitable atmosphere is a nitrogen or argon atmosphere.

A suitable condition may also include a suitable time duration that oneor more steps of the method lasts. In certain embodiments, the suitabletime duration is in the order of minutes (e.g., about 30 min), hours(e.g., about 1 hour, about 2 hours, about 3 hours, about 6 hours, orabout 12 hours), days (e.g., about 1 day or about 2 days) or weeks(e.g., about 1 week). For example, in the step of lowering thetemperature of the mixture, the temperature of the mixture may belowered over a suitable time duration described herein.

Treatment Methods

The present disclosure contemplates the treatment or prophylaxis of adisease of the central nervous system, such as mood disorders (e.g.,depression), anxiety disorders, and neurodegenerative diseases. The termneurodegenerative disease encompasses a condition leading to theprogressive loss of structure or function of neurons, including death ofneurons. Examples of neurodegenerative diseases contemplated hereininclude AIDS dementia complex, adrenoleukodystrophy, alexander disease,Alpers' disease, amyotrophic lateral sclerosis, ataxia telangiectasia,Batten disease, bovine spongiform encephalopathy, brainstem andcerebellum atrophy, Canavan disease, corticobasal degeneration,Creutzfeldt-Jakob disease, dementia with Lewy bodies, fatal familialinsomnia, Friedrich's ataxia, familial spastic paraparesis,frontotemporal lobar degeneration, Huntington's disease, infantileRefsum disease, Kennedy's disease, Krabbe disease, Lyme disease,Machado-Joseph disease, monomelic amyotrophy, multiple sclerosis,multiple system atrophy, neuroacanthocytosis, Niemann-Pick disease,neurodegeneration with brain iron accumulation, opsoclonus myoclonus,Parkinson's disease, Pick's disease, primary lateral sclerosis,progranulin, progressive multifocal leukoencephalopathy, progressivesupranuclear palsy, protein aggregation, Refsum disease, Sandhoffdisease, diffuse myelinoclastic sclerosis, Shy-Drager syndrome,spinocerebellar ataxia, spinal muscular atrophy, spinal and bulbarmuscular atrophy, subacute combined degeneration of spinal cord, Tabesdorsalis, Tay-Sachs disease, toxic encephalopathy, transmissiblespongiform encephalopathy, and Wobbly hedgehog syndrome.

In certain embodiments, compound 1, and/or one or more pharmaceuticalcompositions of compound 1, can be used to treat, ameliorate the signsand/or symptoms of, prevent, or otherwise delay the onset or developmentof the CNS disease, disorder, or condition.

Taught herein, therefore, is the use of compound 1, and/or one or morepharmaceutical compositions of compound 1 described herein, or apharmaceutically acceptable preparation thereof, in the manufacture of amedicament for treating and/or preventing central nervous systemdisorders, such as mood disorders (e.g., depression), anxiety disorders,or neurodegenerative diseases, in a subject in need thereof.

Also provided herein are methods of treating and/or preventing centralnervous system disorders, such as mood disorders (e.g., depression),anxiety disorders, or neurodegenerative diseases comprising theadministration of an effective amount of compound 1, and/or one or morepharmaceutical compositions of compound 1 described herein, or apharmaceutically acceptable preparation thereof, to a subject in needthereof.

As used herein mood disorders are broadly recognized and clearly definedby the relevant DSM-IV-TR (Diagnostic and Statistical Manual of MentalDisorders, 4th Edition, Text Revision) criteria. Thus, there aredepressive disorders of which the best known and most researched ismajor depressive disorder (MDD) commonly called clinical depression ormajor depression, and bipolar disorder (BD), formerly known as manicdepression and characterized by intermittent episodes of mania orhypomania, usually interlaced with depressive episodes. Other depressivedisorders include: atypical depression, melancholic depression,psychotic major depression, catatonic depression, postpartum depression,seasonal affective disorder, dysthymia, depressive disorder nototherwise specified (DD-NOS) (e.g., recurrent brief depression, minordepressive disorder), substance induced mood disorders (e.g., alcoholinduced mood disorders, benzodiazepine induced mood disorders,interferon-alpha induced mood disorders).

Persons of skill in the art will be familiar with the lag period oftraditional antidepressant medications, and with the heightened anxietyproduced by the newer generation antidepressants, including SSRI's,SNRI's and NRI's in the early stages of treatment before theantidepressant effects are seen (within 2-4 weeks). Thus, in certainembodiments, the compounds described herein can be administered to asubject in need thereof as a substitute or replacement for traditionalantidepressant medication. In other embodiments, compounds describedherein can be administered to a subject in need thereof as a supplementto traditional antidepressant medication. In other embodiments, there isprovided a method for treating or preventing depression in a subject,the method including the step of administering to said subject acompound (e.g., Form B of compound 1), or an embodiment thereof,described herein, or a pharmaceutical composition thereof, in theabsence of adjunct antidepressant therapy.

Replacing traditional antidepressant medication with the presentcompounds can be advantageous, particularly where the traditionalmedication is associated with one or more adverse effects (e.g.,anxiety, nausea, headaches, erectile dysfunction, early-onset suicidaltendencies, etc). Examples of traditional antidepressant medicationwould be known to those skilled in the art and include, but are notlimited to, selective serotonin re-uptake inhibitors (SSRI),serotonin/noradrenalin re-uptake inhibitors, selective noradrenalinre-uptake inhibitors, monoamine oxidase inhibitors, tricyclicantidepressants, lithium and other mood stabilisers, atypicalantidepressants, and hormones such as estrogen or progestogen.

In other embodiments, the present compounds are administered to asubject in need thereof, together with traditional antidepressants for aperiod of about 2-4 weeks, to address the symptoms of depression, withthe option of discontinuing treatment with the present compounds whilstcontinuing with the traditional therapy. In other embodiments, thesubject is treated with both a present compound and one or moretraditional antidepressant medications (administered sequentially or incombination) for the duration of the treatment period. Such combinationtherapy may be particularly useful, for example, where the combinationof a present compound and one or more traditional antidepressantmedications provides relief from depression in the acute lag phase ofthe treatment period and/or where an additive or synergisticantidepressant therapeutic effect is desired.

Depression relapse can also occur in patients treated with traditionalantidepressant medication. Many such compounds are administered foranywhere from months to years and a reduction in efficacy is often seenwith such long-term use, leading to significant continuing depressionand dysfunction. Depression relapse may be sudden onset for somepatients, while for others it might be evident as a gradual decline inmood and function, which diminishes over time as the patient approachesthe state of relapse. Thus, patients who experience sudden onset ofdepression relapse or a gradual depression relapse would benefit fromthe methods disclosed herein, as the present compound, or pharmaceuticalcompositions thereof, can offset the diminishing effect of traditionalantidepressant therapy. Thus, the use of the present compound, orpharmaceutical compositions thereof may prevent or partly alleviatedepression relapse often seen in patients taking traditionalantidepressant medication.

Thus, in certain embodiments, provided herein are methods for treatingor preventing relapse in a subject receiving antidepressant therapy, themethod including the step of administering to said subject Form B ofcompound 1, or a pharmaceutical composition thereof.

The traditional antidepressant therapies that are associated withpotential depression relapse in a subject would be known to thoseskilled in the art. Examples include, but are not limited to, dosageincreases, alternative SSRIs or SNRIs, and non-SSRI antidepressants suchas noradrenaline re-uptake inhibitors, monoamine oxidase inhibitors,tricyclic antidepressants, lithium and other mood stabilisers, atypicalantidepressants and hormones such as estrogen and progestogen, alsoreferred to herein as “second antidepressant compounds.”

The desired therapeutic activity, or effect, will typically depend onthe condition being treated. For example, where the subject is beingtreated for depression, the therapeutic effect may be a reduction in atleast one clinical symptom of depression, including, but not limited to,cognitive impairment, loss of appetite, mood, and/or inactivity.

In certain embodiments, compound 1, or pharmaceutical compositionsthereof described herein, or a pharmaceutically acceptable preparationthereof, is administered to said subject sequentially (i.e., before orafter) or in combination with a second antidepressant compound (e.g.,with existing antidepressant therapy).

In certain embodiments, the present compound, or pharmaceuticalcompositions thereof, have the further added advantage over traditionaltherapy in that they exhibit reduced sedative side effects which mayadversely affect a subject's quality of life. In certain embodiments,the present compound, or pharmaceutical compositions thereof, are freeof measurable sedative side effects.

Sudden discontinuation of antidepressant medication may producewithdrawal effects caused by physical dependence on the drug. Compoundscan be evaluated for physical dependence in a simple animal model where,following a period of chronic dosing (e.g., for 14-20 days), the studydrug is stopped and measurements of food intake, body weight and bodytemperature are taken over the next 5 days. The symptoms of abruptdiscontinuation of the drug are manifest as significantly reducedappetite, weight loss, and drop in body temperature. This model issuitable for detecting the effects across a broad range of drug classesincluding opiates, antidepressants, and benzodiazepines. The compound,or pharmaceutical compositions thereof described herein also can be usedas a combination therapy, e.g., combining the treatment with otherantidepressants such as benzodiazepines (e.g., alprazolam, diazepam,lorazepam, clonezepam), selective serotonin re-uptake inhibitors (SSRI)(e.g., citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine,indalpine, paroxetine, sertraline, zimelidine, vilaxodone), serotoninnorepinephrine reuptake inhibitors (SNRI) (e.g., venlafaxine,duloxetine, desvenlafaxine, milnacipran), monoamine oxidase inhibitors(e.g., phenelzine, moclobemide), tricyclic antidepressants (e.g.,trimipramine, imipramine), tetracyclic antidepressants (e.g.,mertazepine, maprotiline), mood stabilisers (e.g. lithium, sodiumvalproate, valproic acid), atypical antidepressants (e.g., bupropion),acetylcholinesterase inhibitors (e.g., donepezil, galantamine,rivastigmine), atypical antipsychotics (e.g., risperidone, aripiprizole,quetiapine, olanzapine), and hormones such as estrogen and progestogen.

It will thus be understood that compound 1, or pharmaceuticalcompositions thereof, can be used in the treatment and/or prevention ofany disease state, disorder, or condition which may be ameliorated byenhancement of neurite outgrowth.

In certain embodiments, the neurite outgrowth-responsive disease is aneurodegenerative disease. In a certain embodiments, theneurodegenerative disease is multiple sclerosis or a Parkinsonianrelated disorder. In a further embodiment, the neurodegenerative diseaseis multiple sclerosis. In a further embodiment the disease may involve acondition which involves neural damage including wound healing, spinalcord injury, peripheral nerve disorders.

Also contemplated herein is a sub-threshold disease, condition, state,disorder or trauma. In an embodiment, the disease, condition, state,disorder, or trauma is defined by its symptoms. Hence, compound 1, or apharmaceutical composition thereof contemplated herein, is useful inameliorating the symptoms of a disease, condition, state, disorder, ortrauma of the CNS. By “trauma” this includes stroke, brain haemorrhage,or another condition or event of the systemic vasculature which affectsthe CNS. The symptoms of a disease, condition, state, disorder, ortrauma of the CNS would be familiar to those skilled in the art.Examples of such symptoms include mood disorders, such as depression.Thus, in certain embodiments, the compound forms described herein areused in the treatment of depression attributed to (or associated with) aneurodegenerative disease in the subject.

The compound forms described herein may also be used as therapy, e.g.,combining the treatment with other neurodegenerative treatments, such asacetylcholineesterase inhibitors (e.g., Aricept, Exelon), and treatmentsfor multiple sclerosis (e.g., Avonex, Betaseron, Copaxone, Tysabri,Gilenya).

In a further embodiment there is also provided a method of treatment ofdisorders of the central nervous system comprising the administration ofan effective amount of compound 1, or a pharmaceutical compositionthereof, to a subject in need thereof.

It will be understood that compound 1, or a pharmaceutical compositionthereof as described herein, can be used in the treatment of anxiety orconditions/disease states associated with anxiety such as irritablebowel syndrome and fibromyalgia.

In certain embodiments, an anxiety disorder is classified as one of thefollowing:

-   panic disorder,-   obsessive-compulsive disorder (OCD),-   post-traumatic stress disorder (PTSD),-   social phobia (or social anxiety disorder—SAD),-   specific phobias,-   generalized anxiety disorder (GAD),-   substance-induced anxiety disorder, and-   acute stress disorder (ASD).

In certain embodiments, compound 1, or a pharmaceutical compositionthereof, as described herein may be used in the treatment of a panicdisorder.

In certain embodiments, compound 1, or a pharmaceutical compositionthereof, as described herein may be used in the treatment ofobsessive-compulsive disorder (OCD).

In certain embodiments, compound 1, or a pharmaceutical compositionthereof, as described herein may be used in the treatment ofpost-traumatic stress disorder (PTSD).

In an embodiment compound 1, or a pharmaceutical composition thereof, asdescribed herein may be used in the treatment of social phobia (orsocial anxiety disorder —SAD).

In certain embodiments, compound 1, or a pharmaceutical compositionthereof, as described herein may be used in the treatment of specificphobias. In certain embodiments, compound 1 or a pharmaceuticalcomposition thereof, as described herein may be used for agoraphobia oragoraphobia without history of panic disorder. In certain embodiments,compound 1 or a pharmaceutical composition thereof, as described hereinmay be used for animal phobia.

In certain embodiments, compound 1, or a pharmaceutical compositionthereof, as described herein may be used in the treatment ofsubstance-induced anxiety disorder.

In certain embodiments, compound 1, or a pharmaceutical compositionthereof, as described herein may be used in the treatment of acutestress disorder (ASD).

In certain embodiments, compound 1, or a pharmaceutical compositionthereof, as described herein may be used in the treatment of generalizedanxiety disorder (GAD).

Generalised anxiety disorder criteria include:

-   (i) At least 6 months of “excessive anxiety and worry” about a    variety of events and situations. Generally, “excessive” can be    interpreted as more than would be expected for a particular    situation or event. Most people become anxious over certain things,    but the intensity of the anxiety typically corresponds to the    situation.-   (ii) There is significant difficulty in controlling the anxiety and    worry. If someone has a very difficult struggle to regain control,    relax, or cope with the anxiety and worry, then this requirement is    met.-   (iii) The presence for most days over the previous six months of 3    or more (only 1 for children) of the following symptoms:-   1. Feeling wound-up, tense, or restless-   2. Easily becoming fatigued or worn-out-   3. Concentration problems-   4. Irritability-   5. Significant tension in muscles-   6. Difficulty with sleep-   (iv) The symptoms are not part of another mental disorder.-   (v) The symptoms cause “clinically significant distress” or problems    functioning in daily life. “Clinically significant” is the part that    relies on the perspective of the treatment provider. Some people can    have many of the aforementioned symptoms and cope with them well    enough to maintain a high level of functioning.-   (vi) The condition is not due to a substance or medical issue.

In certain embodiments, a subject to be treated with compound 1, or apharmaceutical composition thereof, as described herein may beidentified by one or more of the above criteria for generalized anxietydisorder.

In certain embodiments, compound 1, or a pharmaceutical compositionthereof, as described herein may be used to treat or prevent one or moresymptoms associated with an anxiety disorder.

Each anxiety disorder has different symptoms, but all the symptomscluster around excessive, irrational fear and dread.

In another embodiment compound 1, or a pharmaceutical compositionthereof, as described herein may be used in the treatment of depression,for instance, major depressive disorder.

Major depressive disorder criteria include:

-   (i) At least five of the following symptoms have been present during    the same 2-week period and represent a change from previous    functioning: at least one of the symptoms is either    -   1) depressed mood or    -   2) loss of interest or pleasure.-   (ii) Depressed mood most of the day, nearly every day, as indicated    either by subjective report (e.g., feels sad or empty) or    observation made by others (e.g., appears tearful).-   (iii) Markedly diminished interest or pleasure in all, or almost    all, activities most of the day, nearly every day (as indicated    either by subjective account or observation made by others).-   (iv) Significant weight loss when not dieting or weight gain (e.g.,    a change of more than 5% of body weight in a month), or decrease or    increase in appetite nearly every day.-   (v) Insomnia or hypersomnia nearly every day.-   (vi) Psychomotor agitation or retardation nearly every day    (observable by others, not merely subjective feelings of    restlessness or being slowed down).-   (vii) Fatigue or loss of energy nearly every day.-   (viii) Feelings of worthlessness or excessive or inappropriate guilt    (which may be delusional) nearly every day (not merely self-reproach    or guilt about being sick).-   (ix) Diminished ability to think or concentrate, or indecisiveness,    nearly every day (either by subjective account or as observed by    others).-   (x) Recurrent thoughts of death (not just fear of dying), recurrent    suicidal ideation without a specific plan, or a suicide attempt or    specific plan for committing suicide-   (xi) The symptoms do not meet criteria for a mixed episode.-   (xii) The symptoms cause clinically significant distress or    impairment in social, occupational, or other important areas of    functioning.-   (xiii) The symptoms are not due to the direct physiological effects    of a substance (e.g. a drug of abuse, a medication) or a general    medical condition (e.g., hypothyroidism).-   (xiv) The symptoms are not better accounted for by bereavement,    i.e., after the loss of a loved one, the symptoms persist for longer    than 2 months or are characterized by marked functional impairment,    morbid preoccupation with worthlessness, suicidal ideation,    psychotic symptoms, or psychomotor retardation.

The above criteria have been sourced from the American PsychiatricAssociation (2000) Diagnostic and Statistical Manual of Mental Disorders(4th Ed., Text Revision). Washington DC: American PsychiatricAssociation.

In certain embodiments, a subject to be treated with compound 1, or apharmaceutical composition thereof, as described herein may beidentified by one or more of the above criteria for major depressivedisorder.

In another embodiment compound 1, or a pharmaceutical compositionthereof, as described herein may be used to treat or prevent one or moresymptoms associated with depression.

Further disorders for which compound 1, or a pharmaceutical compositionthereof, as described herein may be of benefit include pain andnociception; emesis, including acute, delayed and anticipatory emesis,in particular emesis induced by chemotherapy or radiation, as well asmotion sickness, and post-operative nausea and vomiting; eatingdisorders including anorexia nervosa and bulimia nervosa; premenstrualsyndrome; muscle spasm or spasticity, e.g. in paraplegic subjects;hearing disorders, including tinnitus and age-related hearingimpairment; urinary incontinence; and the effects of substance abuse ordependency, including alcohol withdrawal, neuroses, convulsions,migraine, depressive disorder, bipolar disorder, psychotic disorder,neurodegeneration arising from cerebral ischemia, attention deficithyperactivity disorder, Tourette's syndrome, speech disorder, disordersof circadian rhythm, single-episode or recurrent major depressivedisorder, dysthymic disorder, bipolar I or bipolar II manic disorder,cyclothymic disorder, schizophrenia, and stuttering.

In an embodiment compound 1, or a pharmaceutical composition thereof, asdescribed herein may be used in the treatment of cerebral ischemia. Incertain embodiments, compound 1, or a pharmaceutical compositionthereof, as described herein may be used in the treatment ofneurodegeneration arising from cerebral ischemia.

In an embodiment compound 1, or a pharmaceutical composition thereof, asdescribed herein may be used in the treatment of disorders of thecircadian rhythm.

In an embodiment compound 1, or a pharmaceutical composition thereof, asdescribed herein may be used in the treatment of pain and nociception.

In an embodiment compound 1, or a pharmaceutical composition thereof, asdescribed herein may be used in the treatment of Alzheimer's disease.

It should be appreciated that compound 1, or a pharmaceuticalcomposition thereof, a described herein can be administered to a subjectin a treatment effective amount. In some embodiments, a treatmenteffective amount is a therapeutically effective amount or aprophylactically effective amount. The term “therapeutically effectiveamount” as used herein means that amount of active compound orpharmaceutical agent that elicits the biological or medicinal responsein a tissue, system, animal or human that is being sought by aresearcher, veterinarian, medical doctor, or other clinician. Thetherapeutically effective amount of the compound to be administered willbe governed by such considerations, and is the minimum amount necessaryto ameliorate, cure, or treat the disease or disorder or one or more ofits symptoms. The term “prophylactically effective amount” refers to anamount effective in preventing or substantially lessening the chances ofacquiring a disease or disorder or in reducing the severity of thedisease or disorder before it is acquired or reducing the severity ofone or more of its symptoms before the symptoms develop. Roughly,prophylactic measures are divided between primary prophylaxis (toprevent the development of a disease or symptom) and secondaryprophylaxis (whereby the disease or symptom has already developed andthe subject is protected against worsening of this process).

As used herein, the term “effective amount” relates to an amount of acompound, or pharmaceutical composition thereof, which, whenadministered according to a desired dosing regimen, provides the desiredtherapeutic activity. Dosing may occur at intervals of minutes, hours,days, weeks, months or years or continuously over any one of theseperiods. Suitable dosages lie within the range of about 0.1 ng per kg ofbody weight to 1 g per kg of body weight per dosage. The dosage may bein the range of 1 μg to 1 g per kg of body weight per dosage, such as isin the range of 1 mg to 1 g per kg of body weight per dosage. In oneembodiment, the dosage may be in the range of 1 mg to 500 mg per kg ofbody weight per dosage. In another embodiment, the dosage may be in therange of 1 mg to 250 mg per kg of body weight per dosage. In yet anotherembodiment, the dosage may be in the range of 1 mg to 100 mg per kg ofbody weight per dosage, such as up to 50 mg per body weight per dosage.

In certain embodiments, a provided method comprises administering to asubject in need thereof the present compound, or pharmaceuticalcomposition thereof, in a dosage to provide an effective amount in vivothat will enhance neurite outgrowth (neurogenesis), including, but notlimited to the acute stages of treatment (e.g., within 1, 2, 3, or 4weeks from the commencement of treatment). In an embodiment, aneffective amount in vivo has an in vitro equivalent concentration thatis sufficient to increase neurite outgrowth by at least 5%, at least10%, at least 20%, or at least 50% in a neurite outgrowth assay, forexample, a neurite outgrowth assay described herein. Methods ofdetermining an in vitro equivalent concentration of the presentcompounds would be familiar to the skilled artisan. For example, at fromabout 10 minutes to about 60 minutes after administration of the presentcompounds to a subject, a blood sample is taken and assayed by HPLC,ELISA, gas chromatography, or by other suitable assay to determine theconcentration per ml of blood. An equivalent effective concentration canthen be used in an in vitro assay once factors such as the weight of thesubject, the appropriate blood volume of the subject and the appropriaterate of diffusion of the present compound across the blood-brain barrierare taken into account. In another embodiment, when the present compoundis found to stimulate neurite outgrowth in vitro (as compared to acontrol), an approximate in vivo effective amount can be determined fora subject by extrapolating the in vitro concentration to an in vivoequivalent. Factors such as the weight of the subject, the appropriateblood volume of the subject and the appropriate rate of diffusion of thepresent compound across the blood-brain barrier may be used toextrapolate an in vivo effective amount and hence the appropriate dosageamount that would give rise to said in vivo effective amount.

Thereafter, treatment with the compound 1, or a pharmaceuticalcomposition thereof, may be continued throughout the treatment period orit may be ceased or replaced with traditional therapeutic compounds.Methods of determining the effective amount of compound 1, or apharmaceutical composition thereof, that is required for enhancingneurite outgrowth (neurogenesis) in vivo would be familiar to thoseskilled in the art. For example, enhancement of neurogenesis can bedetermined by measuring a symptom of the CNS disorder including, but notlimited to, cognitive impairment, degree and frequency of seizures ortremors, motordysfunction, headaches and mood (e.g., degree ofhappiness).

The terms “administer”, “administering” or “administration” in referenceto a compound, composition or formulation of the invention meansintroducing the compound into the system of the animal in need oftreatment. When a compound of the invention is provided in combinationwith one or more other active agents, “administration” and its variantsare each understood to include concurrent and/or sequential introductionof the compound and the other active agents.

In certain embodiments, an effective amount of compound 1, or apharmaceutical composition thereof, for administration one or more timesa day to a 70 kg adult human may comprise about 0.0001 mg to about 3000mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg,about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg toabout 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about1000 mg, of a compound per unit dosage form.

In certain embodiments, compound 1, or a pharmaceutical compositionthereof, may be at dosage levels sufficient to deliver from about 0.001mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, fromabout 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg toabout 10 mg/kg, and from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Suitable dosage amounts and dosing regimens can be determined by theattending physician and may depend on the particular condition beingtreated, the severity of the condition as well as the general age,health and weight of the subject. It will be appreciated that doseranges as described herein provide guidance for the administration ofprovided pharmaceutical compositions to an adult. The amount to beadministered to, for example, a child or an adolescent can be determinedby a medical practitioner or person skilled in the art and can be loweror the same as that administered to an adult.

The active ingredient may be administered in a single dose or a seriesof doses. While it is possible for the active ingredient to beadministered alone, it is preferable to present it as a composition,preferably as a pharmaceutical composition. The formulation of suchcompositions is well known to those skilled in the art. The compositionmay contain any suitable carriers, diluents or excipients. These includeall conventional solvents, dispersion media, fillers, solid carriers,coatings, antifungal and antibacterial agents, dermal penetrationagents, surfactants, isotonic and absorption agents and the like. Itwill be understood that the compositions of the invention may alsoinclude other supplementary physiologically active agents.

The compounds and pharmaceutical compositions described herein can beused in combination therapy with one or more additional therapeuticagents. For combination treatment with more than one active agent, wherethe active agents are in separate dosage formulations, the active agentsmay be administered separately or in conjunction. In addition, theadministration of one element may be prior to, concurrent to, orsubsequent to the administration of the other agent.

When co-administered with other agents, e.g., when co-administered withanother anti-anxiety or anti-depressant medication, an “effectiveamount” of the second agent will depend on the type of drug used.Suitable dosages are known for approved agents and can be adjusted bythe skilled artisan according to the condition of the subject, the typeof condition(s) being treated and the amount of a compound describedherein being used. In cases where no amount is expressly noted, aneffective amount should be assumed. For example, compounds describedherein can be administered to a subject in a dosage range from betweenabout 0.01 to about 10,000 mg/kg body weight/day, about 0.01 to about5000 mg/kg body weight/day, about 0.01 to about 3000 mg/kg bodyweight/day, about 0.01 to about 1000 mg/kg body weight/day, about 0.01to about 500 mg/kg body weight/day, about 0.01 to about 300 mg/kg bodyweight/day, about 0.01 to about 100 mg/kg body weight/day.

When “combination therapy” is employed, an effective amount can beachieved using a first amount of compound 1, or a pharmaceuticalcomposition thereof, and a second amount of an additional suitabletherapeutic agent.

In certain embodiments, compound 1 or a pharmaceutical compositionthereof as described herein, and the additional therapeutic agent areeach administered in an effective amount (i.e., each in an amount whichwould be therapeutically effective if administered alone). In otherembodiments, compound 1 or a pharmaceutical composition thereof asdescribed herein, and the additional therapeutic agent are eachadministered in an amount which alone does not provide a therapeuticeffect (a sub-therapeutic dose). In yet other embodiments, compound 1 ora pharmaceutical composition thereof as described herein can beadministered in an effective amount, while the additional therapeuticagent is administered in a sub-therapeutic dose. In still otherembodiments, compound 1 or a pharmaceutical composition thereof asdescribed herein, can be administered in a sub-therapeutic dose, whilethe additional therapeutic agent is administered in an effective amount.

As used herein, the terms “in combination” or “co-administration” can beused interchangeably to refer to the use of more than one therapy (e.g.,one or more prophylactic and/or therapeutic agents). The use of theterms does not restrict the order in which therapies (e.g., prophylacticand/or therapeutic agents) are administered to a subject.

Co-administration encompasses administration of the first and secondamounts of the compounds in an essentially simultaneous manner, such asin a single pharmaceutical composition, for example, capsule or tablethaving a fixed ratio of first and second amounts, or in multiple,separate capsules or tablets for each. In addition, suchco-administration also encompasses use of each compound in a sequentialmanner in either order. When co-administration involves the separateadministration of the first amount of compound 1 or a pharmaceuticalcomposition thereof as described herein, and a second amount of anadditional therapeutic agent, the compounds are administeredsufficiently close in time to have the desired therapeutic effect. Forexample, the period of time between each administration which can resultin the desired therapeutic effect, can range from minutes to hours andcan be determined taking into account the properties of each compoundsuch as potency, solubility, bioavailability, plasma half-life, andkinetic profile. For example, compound 1 or a pharmaceutical compositionthereof as described herein, and the second therapeutic agent can beadministered in any order within about 24 hours of each other, withinabout 16 hours of each other, within about 8 hours of each other, withinabout 4 hours of each other, within about 1 hour of each other or withinabout 30 minutes of each other.

More, specifically, a first therapy (e.g., a prophylactic or therapeuticagent such as a compound described herein) can be administered prior to(e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeksbefore), concomitantly with, or subsequent to (e.g., 5 minutes, 15minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks,4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) theadministration of a second therapy to a subject.

Examples of therapeutic agents that may be combined with compound 1, ora pharmaceutical composition thereof, either administered separately orin the same pharmaceutical composition, include, but are not limited to,muscle relaxants, anticonvulsants, hypnotics, anesthetics, analgesics,cholinergics, antidepressants, mood stabilisers, and anxiolytics.

In certain embodiments, a second therapeutic agent is a SSRI selectedfrom the following: citalopram (Celexa, Cipramil, Cipram, Dalsan,Recital, Emocal, Sepram, Seropram, Citox, Cital), dapoxetine (Priligy),escitalopram (Lexapro, Cipralex, Seroplex, Esertia), fluoxetine (Prozac,Fontex, Seromex, Seronil, Sarafem, Ladose, Motivest, Flutop, Fluctin(EUR), Fluox (NZ), Depress (UZB), Lovan (AUS), Prodep (IND)),fluvoxamine (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox),paroxetine (Paxil, Seroxat, Sereupin, Aropax, Deroxat, Divarius,Rexetin, Xetanor, Paroxat, Loxamine, Deparoc), sertraline (Zoloft,Lustral, Serlain, Asentra), and vilazodone (Viibryd).

In certain embodiments, a second therapeutic agent is a tetracyclicantidepressant (TeCA) selected from the group consisting of: amoxapine(Amokisan, Asendin, Asendis, Defanyl, Demolox, Moxadil), maprotiline(Deprilept, Ludiomil, Psymion), mazindol (Mazanor, Sanorex), mianserin(Bolvidon, Depnon, Norval, Tolvon), mirtazapine (Remeron, Avanza,Zispin, Miro), and setiptiline (Tecipul).

In certain embodiments, a second therapeutic agent is aserotonin-noradrenaline reuptake inhibitor (SNRI) selected from thegroup consisting of: desvenlafaxine (Pristiq), duloxetine (Cymbalta,Ariclaim, Xeristar, Yentreve, Duzela), milnacipran (Ixel, Savella,Dalcipran, Toledomin), and venlafaxine (Effexor, Efexor).

In certain embodiments, a second therapeutic agent is a Noradrenalinereuptake inhibitor (NRI) selected from the group consisting of:atomoxetine (Tomoxetine, Strattera, Attentin), mazindol (Mazanor,Sanorex), reboxetine (Edronax, Norebox, Prolift, Solvex, Davedax,Vestra), and viloxazine (Vivalan, Emovit, Vivarint, Vicilan).

In certain embodiments, a second therapeutic agent is a monoamineoxidase inhibitor (MAOI) selected from the group consisting of: benmoxin(Nerusil, Neuralex), hydralazine (Apresoline), iproclozide (Sursum),iproniazid (Marsilid, Iprozid, Ipronid, Rivivol, Propilniazida),isocarboxazid (Marplan), isoniazid (Laniazid, Nydrazid), mebanazine(Actomol), nialamide (Niamid), octamoxin (Ximaol, Nimaol), phenelzine(Nardil, Nardelzine), pheniprazine (Catron), phenoxypropazine (Drazine),pivalylbenzhydrazine (Tersavid), procarbazine (Matulane, Natulan,Indicarb), caroxazone (Surodil, Timostenil), echinopsidine (Adepren),furazolidone (Furoxone, Dependal-M), linezolid (Zyvox, Zyvoxam,Zyvoxid), tranylcypromine (Parnate, Jatrosom), brofaromine (Consonar),metralindole (Inkazan), minaprine (Cantor), moclobemide (Aurorix,Manerix), pirlindole (Pirazidol), toloxatone (Humoryl), lazabemide(Pakio, Tempium), pargyline (Eutonyl), rasagiline (Azilect), andselegiline (Deprenyl, Eldepryl, Emsam).

In certain embodiments, a second therapeutic agent is a tricyclicantidepressant (TCA) selected from the group consisting of:amitriptyline (Tryptomer, Elavil, Tryptizol, Laroxyl, Sarotex,Lentizol), butriptyline (Evadene, Evadyne, Evasidol, Centrolese),clomipramine (Anafranil), desipramine (Norpramin, Pertofrane), dosulepin(Prothiaden, Dothep, Thaden and Dopress), doxepin (Aponal, Adapine,Doxal, Deptran, Sinquan, Sinequan, Zonalon, Xepin, Silenor), imipramine(Antideprin, Deprimin, Deprinol, Depsol, Depsonil, Dynaprin, Eupramin,Imipramil, Irmin, Janimine, Melipramin, Surplix, Tofranil), lofepramine(Gamanil, Tymelyt, Lomont), nortriptyline (Sensoval, Aventyl, Pamelor,Norpress, Allegron, Noritren, Nortrilen), Protriptyline (Vivactil), andtrimipramine (Surmontil, Rhotrimine, Stangyl).

The compounds and compositions provided herein can be administered byany route, including enteral (e.g., oral), parenteral, intravenous,intramuscular, intra-arterial, intramedullary, intrathecal,subcutaneous, intraventricular, transdermal, interdermal, rectal,intravaginal, intraperitoneal, topical (as by powders, ointments,creams, and/or drops), mucosal, nasal, bucal, sublingual; byintratracheal instillation, bronchial instillation, and/or inhalation;and/or as an oral spray, nasal spray, and/or aerosol. Specificallycontemplated routes are oral administration, intravenous administration(e.g., systemic intravenous injection), regional administration viablood and/or lymph supply, and/or direct administration to an affectedsite. In general, the most appropriate route of administration willdepend upon a variety of factors including the nature of the agent(e.g., its stability in the environment of the gastrointestinal tract),and/or the condition of the subject (e.g., whether the subject is ableto tolerate oral administration).

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, severity of the side effects ordisorder, identity of the particular compound(s), mode ofadministration, and the like. The desired dosage can be delivered threetimes a day, two times a day, once a day, every other day, every thirdday, every week, every two weeks, every three weeks, or every fourweeks. In certain embodiments, the desired dosage can be delivered usingmultiple administrations (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or moreadministrations).

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. These examples are forillustrative purposes only and are not to be construed as limiting thisinvention in any manner.

Example 1 General Methods of Instrumental Measurements

FT-Raman Spectroscopy. Bruker RFS100 with OPUS 6.5 software or Multi-RAMwith OPUS 7.0 software; Nd:YAG 1064-nm excitation, Ge detector, 3500-100cm⁻¹ range; typical measurement conditions: 50-300 mW nominal laserpower, 64-128 scans, 2 cm⁻¹ resolution.

XRPD. Bruker D8; reflection geometry, Bragg-Brentano; Cu-K_(α)radiation, 40 kV/40 mA; variable divergence slit; LynxEye detector with3° window; 0.02°2θ step size; 37 s step time. The samples were rotatedduring the measurement. Sample preparation: The samples were generallyprepared without any special treatment other than the application ofslight pressure to get a flat surface. Silicon single crystal sampleholder, 0.1 mm deep.

¹H-NMR. Bruker DPX300 spectrometer; proton frequency of 300.13 MHz; 30°excitation pulse; recycle delay of 1 s; accumulation of 16 scans;deuterated DMSO as the solvent; solvent peak used for referencing;chemical shifts reported on the TMS scale.

TG-FTIR. Netzsch Thermo-Microbalance TG 209 with Bruker FT-IRSpectrometer Vector 22; aluminum crucible (with micro-hole), N₂atmosphere, 10 K/min heating rate, 25-250° C. or 25-350° C. range.

DSC. Perkin Elmer DSC 7; closed gold crucibles, sample filled in an N₂environment, 10 K/min heating rate, −50 to 250° C. range, at timesquench cooling (at −200 K min⁻¹) to −50° C. between scans.

DVS. Projekt Messtechnik Sorptions Prüfsystem SPS 11-100n or SurfaceMeasurement Systems DVS-1. The sample was placed on an aluminum orplatinum holder on top of a microbalance and allowed to equilibrate for2 h at 50% r.h. before starting one of two pre-defined humidityprograms:

(1) 2 h at 50% r.h.;

(2) 50→0% r.h. (5%/h); 5 h at 0% r.h.;

(3) 0→95% r.h. (5%/h); 5 h at 95% r.h.; and

(4) 95→50% r.h. (5%/h); 2 h at 50% r.h.;

or

(1) 2 h at 50% r.h.;

(2) 50→95% r.h. (5%/h); 5 h at 95% r.h.;

(3) 95→0% r.h. (5%/h); 5 h at 0% r.h.; and

(4) 0→50% r.h. (5%/h); 2 h at 50% r.h.

The hygroscopicity was classified based on the mass gain at 85% r.h.relative to the initial mass as follows: deliquescent (sufficient wateradsorbed to form a liquid), very hygroscopic (mass increase of ≧15%),hygroscopic (mass increase <15% and ≧2%), slightly hygroscopic (massincrease <2% and ≧0.2%), or non-hygroscopic (mass increase <0.2%).

Solvents. For all experiments, Fluka, Merck or ABCR analytical gradesolvents were used.

HPLC. HPLC methods given in Table 6 were used. Standard solutions of theSP196-FD-P1 free drug of compound 1 and the L-malate salt of compound 1(SP196-MLA-P4) were prepared in the concentration range of 0.2-0.05mg/mL for the construction of a calibration curve.

TABLE 6 HPLC methods. Instrument Agilent 1100 series Column WatersXterra C18, 100 × 4.6 mm, 5 μm (FK-CC01E) Mobile Phase A H₂O + 0.1% TFAMobile Phase B MeCN Reference conc. 0.2-0.05 mg/mL Retention time 10.48min Gradient  0 min 95% A 5% B 20 min  5% A 95% B  20.5 min   95% A 5% B22 min 95% A 5% B Flow 1.00 mL/min Injection Volume 10 μL Column temp.25° C. Wavelength 240 nm

Example 2 Preparation and Characterization of Form B

3.2 kg of compound 1 containing <0.5% impurity A (compound 2)) wasdissolved in 100 L of methanol with refluxing, and 140 L of water at72-75° C. was added. Upon completion of addition of water, the resultingmixture was allowed to cool very slowly to crystallize out a solid. Thesolid was isolated by filtration to give Form B in about 90% yield.

This method was fine-tuned to work on a kilogram scale. However, theimpurity A was retained in crystallized material. The crystallizationprocedure was modified to remove any acidic impurity by using watercontaining Na₂CO₃ or NaHCO₃. Impurity A (compound 2) level was droppedfrom about 0.8% to about 0.1% after crystallization from MeOH and watercontaining Na₂CO₃ or NaHCO₃. In one set of experiments, 2.36 kg ofcompound 1 (containing 0.85% impurity A) was dissolved in 59 L ofmethanol with refluxing (60-65° C.) and 59 L of water (containing 11.8 gof Na₂CO₃) at 60-65° C. was added. Upon completion of addition of water,the mixture was allowed to cool very slowly to crystallize out a solid.The solid was separated by filtration to give Form B in about 90% yield(containing 0.1% impurity A). FT-Raman spectrum (FIG. 2) shows narrow,intense peaks and no fluorescence.

The XRPD pattern (FIG. 1) confirms the crystallinity of Form B.

The ¹H-NMR spectrum (FIG. 6) agrees with the given structure.

The TG-FTIR thermogram (FIG. 5) shows the loss of about 2.0 wt % H₂Obetween 100° C. and 230° C. and decomposition at >250° C. The water ismost likely bound within the structure. The theoretical water content ofa hemihydrate is 2.1 wt %. Thus, Form B is likely a hemihydrate and/or anon-stoichiometric hydrate.

The DSC thermogram (FIG. 3) shows an endotherm with several shoulders onthe low temperature side and a peak maximum at a T_(max) of about 176.3°C. (ΔH of about 105.4 J/g), most likely corresponding to melting. Afterquench cooling, a glass transition with a T_(g) of about 70.8° C. (ΔCpof about 0.48 J/(g° C.)) was observed in the second heating scan.

During the DVS measurement (FIG. 4), the relative humidity was firstlowered from 50% r.h. to 0% r.h., then raised from 0% r.h. to 95% r.h.and lowered back again to 50% r.h. The sample shows a mass loss of about0.1 wt % upon lowering the relative humidity from 50% r.h. to 0% r.h.Upon increasing the relative humidity to 95% r.h., a gradual mass gainof about 0.3 wt % (relative to the mass at 0% r.h.) was observed. Uponlowering the relative humidity from 95% r.h. to 50% r.h., the final masswas equal to the starting mass. The mass increase of 0.1 wt % at 85%r.h. (relative to the starting mass at 50% r.h.) classifies the sampleas non-hygroscopic.

The FT-Raman spectrum of the sample of Form B after the DVS measurementis unchanged compared to the spectrum before the measurement, indicatingthat no transformation has taken place.

Microscopic images of the sample of Form B show that the sample consistsof very small granular crystals (FIGS. 7A and 7B).

Example 3 Drying of Form B

A solid sample of Form B was dried in an attempt to dehydrate it. Thesample was stored under vacuum (<5 mbar (e.g., about 4 mbar)) at 40° C.overnight or for 1 day.

The XRPD pattern of the dried sample (FIG. 8) is unchanged compared tothe pattern of the sample before drying.

The TG-FTIR thermogram of the dried sample (FIG. 9) shows the loss ofabout 1.9 wt % H₂O from 50° C. to 200° C. and decomposition at atemperature greater than about 200° C.

Thus, the water seems tightly bound within a stable structure, nodehydration and loss of solvent occurred.

Example 4 Stability Study

A sample of Form B was stored at about 25° C. and about 60% r.h. for aperiod of time (e.g., 24 months). The concentration of compound 1 in thesample was assayed using HPLC, XRPD, and IR at different time points.The results are shown in Table 7. The term “complies” refers tosubstantially the same XRPD pattern and/or IR spectrum as the sample atthe incept of the storage (time point=initial).

TABLE 7 Stability of Form B stored at about 25° C. and about 60% r.h.Concentration of compound 1 by HPLC Assay Time point (anhydrous basis)XRPD IR Initial 99.5% w/w  3 months 99.4% w/w complies complies  6months 99.6% w/w complies complies 12 months 99.3% w/w complies complies18 months 99.4% w/w complies complies 24 months 99.2% w/w compliescomplies

The results shown in Table 7 indicate that Form B is stable upon storagefor at least 24 months at about 25° C. and about 60% r.h.

Another sample of Form B was stored at about 40° C. and about 75% r.h.for a period of time (e.g., 6 months). The concentration of compound 1in the sample was assayed using HPLC, XRPD, and IR at different timepoints. The results are shown in Table 8. The term “complies” refers tosubstantially the same XRPD pattern and/or IR spectrum as the sample atthe incept of the storage (time point=initial).

TABLE 8 Stability of Form B stored at about 40° C. and about 75% r.h.Concentration of compound 1 by HPLC Assay Time point (anhydrous basis)XRPD IR Initial 99.5% w/w 1 month 99.6% w/w 2 months 99.3% w/w 3 months99.3% w/w complies complies 6 months 99.4% w/w complies complies

The results shown in Table 8 indicate that Form B is stable upon storagefor at least 6 months at about 40° C. and about 75% r.h.

Equivalents and Scope

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

The reference in this specification to any prior publication (orinformation derived from it), or to any matter which is known, is not,and should not be taken as an acknowledgment or admission or any form ofsuggestion that that prior publication (or information derived from it)or known matter forms part of the common general knowledge in the fieldof endeavour to which this specification relates.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

What is claimed is:
 1. A method of preparing a crystalline Form B ofcompound I of formula:

the method comprising mixing a solution of compound 1 in methanol withan aqueous solution of a base to provide a mixture.
 2. The method ofclaim 1, further comprising lowering the temperature of the mixture toprovide a solid.
 3. The method of claim 2, further comprising isolatingthe solid from the mixture.
 4. The method of claim 1 wherein the base isselected from the group consisting of Na₂CO₃ and NaHCO₃.
 5. The methodof claim 4 wherein the base is Na₂CO₃.
 6. The method of claim 1 whereinForm B is prepared in greater than 99% purity.
 7. The method of claim 1wherein the crystalline Form B is a hydrate.
 8. The method of claim 1wherein the crystalline Form B is a hemihydrate.
 9. The method of claim1 wherein the crystalline Form B is a non-stoichiometric hydrate. 10.The method of claim 1 wherein the crystalline Form B is substantiallyfree of amorphous compound
 1. 11. The method of claim 1 wherein thecrystalline Form B is characterized by having four or more peaks in itsXRPD pattern selected from those in the following table: Angle 2-Theta °13.94 14.52 16.27 16.60 17.62 18.76 19.02 19.29 19.64 22.32 22.77 23.02 23.16.


12. The method of claim 1 wherein the crystalline Form B ischaracterized by a Raman spectrum with characteristic peaks selectedfrom those in the following table: Wavenumber (cm⁻¹) 3322 3070 3007 29932963 2931 2910 2871 2842 1636 1611 1604 1508 1497 1478 1459 1446 14251393 1355 1344 1319 1304 1285 1271 1243 1225 1208 1150 1136 1112 10951064 1039 1025 1010 996 957 943 849 819 810 789 741 713 681 603 585 555501 484 446 419 372 349 316 261 234 185
 141.


13. The method of claim 1 wherein the crystalline Form B ischaracterized by a DSC thermogram with an endotherm having a peaktemperature (T_(max)) of about 176° C.
 14. The method of claim 1 whereinthe crystalline Form B is characterized by a DSC thermogram with a ΔH ofabout 105 J/g.
 15. The method of claim 1 wherein the crystalline Form Bis characterized by a glass transition (T_(g)) of about 71° C. afterquench cooling.
 16. The method of claim 1 wherein the crystalline Form Bis characterized by a ΔC_(p) of about 0.48 J/(g° C.) after quenchcooling.